I just e-mailed suggesting umbrella sampling. Since you put some more detail in your question, I'll give you a bit more detail in terms of how you might go about doing that.
I didn't get a response to this question before, so here I go again: I have a protein that has a residue modeled as a 2-state rotamer in the crystal structure. The transition occurs in ms, so I cannot see it in the MD simulations. I'd like to calculate the free energy difference between both states, possibly using the perturbation method. But I am not sure how to do this, as examples are usually done for mutations and hydration. Has anyone an idea of how to do this? So far I have thought of changing the dihedral of the side chain in the top file (which goes from avge -90 to 90), but I am thinking that maybe there are other things that I need to account for. Any ideas …?
In my opinion, the easiest way to do this is to run a series of separate calculations where the dihedral is restrained to a particular value using simple harmonic restraints (make sure you are using 3.3.1 or 3.3 with relevant bugfixes, as dihedral restraints were broken previously). You can do this by just putting a [ dihedral_restraints ] section in your topology (see the documentation). You restrain to a series of different angles to cover the whole 360^o of interest, and then use the weighted histogram analysis method (WHAM) to take the potential energies and calculate a potential of mean force (PMF) -- basically the free energy profile for rotating the dihedral. The free energy difference is then the appropriately weighted difference of the log probability of being in each basin. (As a first approximation you can just take the difference in well depths, but it isn't quite right, especially if they have different shapes). There is in principle a WHAM code in gromacs (g_wham), but I haven't used it and can't vouch for it, and it probably expects some input other than just the results of a bunch of separate simulations with different dihedral restraints, so if you use my route, it probably means you need your own WHAM code (or ask us for ours). Alternatively, there is probably some way you can do the whole umbrella sampling and PMF routine in GROMACS alone using g_wham, but I can't help you with that. Things to watch out for: - Make sure if you look at the binned dihedral angles, you have good enough overlap in the distributions, otherwise your free energy differences will be wrong - Make sure your spring constant is big enough to ensure you sample across the barriers (and you equilibrate long enough), but not so big that you get delta function-type probability distributions. The overlap thing is key. Otherwise you will get a PMF that looks OK (maybe), but is completely wrong. David
Thanks!! Esther Caballero-Manrique Graduate Teaching Fellow Chemistry Department 1253 University of Oregon Eugene, OR 97403-1253 (541) 346-2485 _______________________________________________ gmx-users mailing list [email protected] http://www.gromacs.org/mailman/listinfo/gmx-users Please don't post (un)subscribe requests to the list. Use the www interface or send it to [EMAIL PROTECTED] Can't post? Read http://www.gromacs.org/mailing_lists/users.php
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